Kuzman, Drago, Bunc, Marko, Reiter, Fritz, Boncina, Matjaz, Žagar, Lan and Ravnik , Miha (2021) Long-Term Stability Predictions of Therapeutic Monoclonal Antibodies in Solution Using Arrhenius Based Kinetics. Scientific reports, 11 (20534).

Abstract

Long-term stability of monoclonal antibodies is the key aspect in their development for use as (bio)pharmaceutical products; therefore, possible prediction of long-term stability from accelerated stability studies is of major interest, despite currently regarded as not sufficiently robust. In this work, using combination of accelerated stability studies (up to 6 months) and first order degradation kinetic modelling, we are able to predict long-term stability (up to 3 years) including temperature dependence of changes of multiple quality attributes and for multiple monoclonal antibody formulations. More specifically, we can robustly predict the long-term stability behavior of a protein at the intended storage condition (5°C), based on up to six months data obtained from different temperatures, usually from intended (5°C), accelerated (25°C) and stress conditions (40°C). We have performed stability studies and evaluated the stability data of several mAbs including IgG1, IgG2, IgG4 and fusion proteins and validated our model by overlaying the 95% prediction interval and experimental stability data from up to 36 months. We demonstrated improved robustness, speed and accuracy of kinetic long-term stability prediction as compared to classical linear extrapolation used today, justifying long-term stability prediction and shelf life extrapolation for some biological products such as monoclonal antibodies. More generally, this work aims to contribute towards further development and refinement of the regulatory landscape that will allow extrapolation for biological products during the developmental phase, clinical phase and also in marketing authorization applications, as already established today for small molecules.

Item Type:	Article
Keywords:	biopharmaceutics, proteins, stability, Arrhenius equation, stability prediction, shelf life, monoclonal antibodies, kinetics, quality attributes
Date Deposited:	09 Nov 2021 00:45
Last Modified:	09 Nov 2021 00:45
URI:	https://oak.novartis.com/id/eprint/45143